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other·ophthalmology, retina, preclinical research, biomedical research·PMC10483287

Integration of human stem cell-derived in vitro systems and mouse preclinical models identifies complex pathophysiologic mechanisms in retinal dystrophy

Frontiers in Cell and Developmental Biology · 9 authors, 7 centres

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TL;DR

Two independent DRAM2 biallelic knockout hPSC lines were generated via CRISPR/Cas9 and differentiated into retinal organoids matured for 12 months.

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Two independent DRAM2 biallelic knockout hPSC lines were generated via CRISPR/Cas9 and differentiated into retinal organoids matured for 12 months. 1 cell per WT) localized near RPE cells, with no other significant transcriptional differences. The authors note limitations including reliance on mRNA rather than protein-level data, use of developmental rather than aged models, and knockout rather than patient-mutation approaches.

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other

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ophthalmology

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ORIGINAL PAPER

PMC10483287

Integration of human stem cell-derived in vitro systems and mouse preclinical models identifies complex pathophysiologic mechanisms in retinal dystrophy

Frontiers in Cell and Developmental Biology

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ABSTRACT

Abstract Rare DRAM2 coding variants cause retinal dystrophy with early macular involvement via unknown mechanisms. We found that DRAM2 is ubiquitously expressed in the human eye and expression changes were observed in eyes with more common maculopathy such as Age-related Macular Degeneration (AMD). To gain insights into pathogenicity of DRAM2-related retinopathy, we used a combination of in vitro and in vivo models. We found that DRAM2 loss in human pluripotent stem cell (hPSC)-derived retinal organoids caused the presence of additional mesenchymal cells. Interestingly, Dram2 loss in mice also caused increased proliferation of cells from the choroid in vitro and exacerbated choroidal neovascular lesions in vivo . Furthermore, we observed that DRAM2 loss in human retinal pigment epithelial (RPE) cells resulted in increased susceptibility to stress-induced cell death in vitro and that Dram2 loss in mice caused age-related photoreceptor degeneration. This highlights the complexity of DRAM2 function, as its loss in choroidal cells provided a proliferative advantage, whereas its loss in post-mitotic cells, such as photoreceptor and RPE cells, increased degeneration susceptibility. Different models such as human pluripotent stem cell-derived systems and mice can be leveraged to study and model human retinal dystrophies; however, cell type and species-specific expression must be taken into account when selecting relevant systems. Keywords: retinal dystrophy, human stem cells, retinal organoids, mouse models, single cell sequencing, DRAM2 , disease modeling

CITATION EXPORT

Melissa K Jones, Luz D Orozco, Han Qin et al.. Integration of human stem cell-derived in vitro systems and mouse preclinical models identifies complex pathophysiologic mechanisms in retinal dystrophy. Frontiers in Cell and Developmental Biology. (2023). https://doi.org/10.3389/fcell.2023.1252547

AUTHORS

9 · 7 CENTRES

Melissa K Jones, Luz D Orozco, Han Qin, Tom Truong, Patrick Caplazi, Justin Elstrott, Zora Modrusan, Shawnta Y Chaney, Marion Jeanne

1 Department of Neuroscience, Genentech Inc., South San Francisco, CA, United States
2 Product Development Clinical Science Ophthalmology, Genentech Inc., South San Francisco, CA, United States
3 Department of Bioinformatics, Genentech Inc., South San Francisco, CA, United States
4 Department of Translational Immunology, Genentech Inc., South San Francisco, CA, United States
5 Department of Research Pathology, Genentech Inc., South San Francisco, CA, United States
6 Department of Translational Imaging, Genentech Inc., South San Francisco, CA, United States
7 Department of Microchemistry, Proteomics, Lipidomics and Next-Generation Sequencing, Genentech Inc., South San Francisco, CA, United States